The basal ganglia (BG) are a group of subcortical brain nuclei in the central nervous system (CNS) that are intimately involved in movement and cognition17, 27, 26. The cerebral cortex, the principal afferent of the BG, directly transfers information to the BG via projections to the neostriatum (NS) and subthalamic nucleus (STN). The STN is a small, deep-lying neural centre in the brain that is critical for movement and some cognitive processes. Although not accounted for in classic models of BG function17, 71, recent studies contend that the input operations of STN are critical for the processing of cortical information in the BG, not least because the corticosubthalamic pathway represents the swiftest route by which the cortex can influence the activity of STN and its targets, the globus pallidus (GP) and the output nuclei of the BG51, 57.
‘Deep brain stimulation’ (DBS) or electrocoagulation, by the use of metal electrodes implanted temporally or permanently in the basal ganglia, have been shown to be effective treatments for epilepsy, dystonia and all major symptoms of Parkinson's disease (PD)41. Essential tremor and parkinsonian tremor can be ameliorated or even abolished by DBS electrical stimulation of the ventral intermediate nucleus (VIM). In PD, DBS of the STN reduces rigidity, tremor and hypokinesia. A prerequisite for a beneficial outcome of patients is the accurate identification of the position of a chosen target nucleus, usually in the basal ganglia or ventral thalamus, so that special emphasis is to be put on procedural aspects of electrode placement34.
Whereas DBS techniques utilise electrical currents to stimulate the target neural centre, electrocoagulation techniques involve the supply of electrical currents to heat the neural centre, effectively burning out the neural centre and destroying its activity.
The accepted method for implantation and positioning of DBS macro-electrodes in the STN comprises an initial imaging step, typically magnetic resonance imaging (MRI)-guided stereotactic localisation, followed by confirmation of the motor territory of the target nucleus by micro-electrode mapping68 and verification of the efficacy of stimulation by trial run.
Whilst MRI and other imaging techniques can provide general information on the location of anatomical structures in a given individual, these techniques often cannot provide detailed information on the exact spatial location of specific neural centres in the BG and, the CNS in general.
Thus to date, high-resolution micro-electrode measurements are used to depict target-specific neuronal discharge patterns of single neurons (aka ‘single units’). The micro-electrode measurements are then used to direct the implantation and positioning of the DBS macro-electrode. High standards of technical equipment and practitioner expertise are required to perform these micro-recordings, both of which are not easily available. Moreover, the use of fine micro-electrodes carries an increased risk of neuronal tissue damage by puncture of blood vessels and neurons during implantation of the micro-electrode.
Thus, the surgical implantation of the requisite electrodes for DBS treatment remains seriously disadvantaged by the difficulties associated with unequivocally identifying the STN itself (i.e. distinguishing the STN from surrounding structures) and, once identified, locating the (motor) area of STN that is most useful for subsequent electrical manipulation.
Micro-electrode measurements are designed to record the activity of single units, which may provide limited, but often characteristic, information as to the position of the electrode and thus, the location of the neural centre of interest. In contrast, field potentials (FPs) measure the activity generated by larger groups of firing neurons.
Field potentials may be generated spontaneously or may be evoked by a stimulus. The nature of the FPs evoked by stimulation is critically dependent on the structure that is itself stimulated. Somatosensory evoked field potentials (SEP) have been recorded in the STN during implantation surgery using the DBS-type macro-electrodes34. SEPs were generated by stimulation of neurons external of the CNS, specifically at the median nerve in the forearm. The low-amplitude and complex profiles of SEPs recorded along STN trajectories precluded the use of these field potentials for identifying STN targets.
Responses of STN neurons to cerebral cortical input are often ‘multiphasic’ and vary according to the differential activation of several distinct BG circuits, including the NS and the reciprocally-connected STN-GP network25, 48, 56, 35. The complex interactions within cortical and basal ganglia circuits make the theoretical extrapolation of single neuron responses, as measured using micro-electrode techniques, to the population level a difficult task.
Accordingly a number of technical difficulties and problems exist in the unequivocal identification of a neural centre in the CNS. In particular, the inaccuracies associated with current methods for identifying the position of neural centres in the BG, such as the STN, and GP provides a significant obstacle to the treatment of patients by electrode-based therapies, such as DBS and electrocoagulation.